Studies are designed to determine which of the major classes of hepatic cells are responsible for the uptake of different lipoproteins by the liver and to define which apoproteins mediate the uptake of lipoproteins by the different cell types. Rat endothelial, Kupffer and parenchymal cells are isolated by collagenase liver perfusion, centrifugation on Percoll gradients and centrifugal elutriation. Apoproteins isolated from normal subjects and patients with Tangier disease have been radioiodinated and reassociated with lipoprotein particles from normal subjects and patients with Tangier disease. Measurements of the uptake of these labeled particles by hepatic cells in vitro indicate that the increased reticuloendothelial (RE) cell uptake of cholesterol in Tangier disease is probably mediated by enhanced uptake of Tangier apoprotein A-I-containing cholesterol-rich lipoproteins by RE cells and that the rapid clearance of lipoproteins from the plasma in Tangier disease can be accounted for by the uptake of Tangier apoprotein A-I-containing lipoproteins by hepatocytes. Thus, in Tangier disease a structurally abnormal apoprotein A-I appears to be responsible for the mediation of hypercabolism of lipoproteins and the abnormal accumulation of lipoproteins in RE cells.